MIELNICKI, Lawrence;SCHENTAG; Jerome;SCHENTAG, Jerome, J.;MCCOURT, Mary, P.; J.
发明人:
SCHENTAG, Jerome, J.,MCCOURT, Mary, P.,MIELNICKI, Lawrence
申请号：
USUS2017/048135
公开号：
WO2018/039303A1
申请日:
2017.08.23
申请国别(地区):
US
年份:
2018
代理人:
摘要：
The present invention is directed to one or more macromolecules in a lipid vesicle oral formulation which targets intracellular receptors, in particular for peptides, proteins, nucleic acids and mixtures thereof, optionally in combination with small molecules. The invention encapsulates said macromolecules in a neutral lipid vesicle comprised of one or more cholesteryl esters. Unique properties of macromolecules encapsulated in said vesicles include high oral bioavailability, defined herein as in at least 50%, i.e., often in excess of 50% on the basis of oral to parenteral AUC. Non-limiting examples are provided, for large hydrophilic molecules such as peptides, proteins and nucleic acids which heretofore have been very poorly absorbed by the mammalian intestine. In prior art； said molecules are generally less than 25% bioavailable, even with protective coatings and optionally absorption enhancing component substances in the formulation. An additional feature of the present invention is high tissue concentrations after oral use, a result of rapid uptake of cholestosomes delivered by chylomicrons to body cells. A preferred embodiment is disclosed for insulin, where with eholestosome encapsulation oral bioavailability is at least 66%. Prior to the present invention, oral bioavailability of insulin and other peptides and proteins was maximally 25% and usually between 5% and 10%. Additional preferred examples are provided for one or more macromolecules useful in the treatment of cancer and in particular intracellular targeting in the practice of cancer immunotherapeutics.La présente invention concerne une ou plusieurs macromolécules dans une formulation orale de vésicule lipidique qui cible des récepteurs intracellulaires, en particulier pour des peptides, des protéines, des acides nucléiques et des mélanges de ceux-ci, éventuellement en combinaison avec de petites molécules. L'invention encapsule lesdites macromolécules dans une vésicule lipidique neutre composée d'un
